Various deoxy derivatives of kanamycin A, B or C have useful antibacterial activities, but the antibacterial spectra of these known deoxy-derivatives of kanamycins are of different ranges. Accordingly, it is always demanded that new, antibacterial compounds having any more excellent properties than the known kanamycin derivatives should be produced and provided.
The present inventors have synthetized 3'-deoxy-3'-fluorokanamycin A (see Japanese patent application first publication "Kokai" No. 40297/86 and U.S. Pat. No. 4,634,688). Further, the present inventors have synthetized 3'-deoxy-3'-fluorokanamycin B and found that 3'-deoxy-3'-fluorokanamycin B has remarkable antibacterial activities against various gram-positive and gram-negative bacteria, including the resistant bacteria (see Japanese patent application first publication "Kokai" No. 140597/86). And, the present inventors have synthetized 3',4'-dideoxy-3'-fluorokanamycin B (see Japanese patent application first publication "Kokai" No. 51694/87 and U.S. Pat. No. 4,845,082 specification).
Furthermore, the present inventors have synthetized 1-N-[(RS)- or (S)-3-amino-2-hydroxy-propionyl]- or 1-N-[(S)-4-amino-2-hydroxybutyryl]-3'-deoxy-3'-fluorokanamycin A or B (see Japanese patent application first publication "Koaki" No. 236791/86).
Moreover, the present inventors have synthetized 2', 3'-dideoxy-2'-fluorokanamycin A (see the specification of Japanese patent application first publication "Kokai" No. 143393/86) as well as 1-N-[(RS)- or (S)-3-amino-2-hydroxypropionyl]- or 1-N-[(S)-4-amino-2-hydroxybutyryl]-2',3'-dideoxy-2'-fluorokanamycin A (see Japanese patent application first publication "Koaki" No. 93296/87 and U.S. Pat. No. 4,661,474specification).
On the other hand, a literature "Aminocyclitol Antibiotics" pages 371-392, edited by K. L. Rinehart and T. Suami (published from American Chemical Society in 1980) discloses the production of 5-deoxy-5-fluoro-5-epi-sisomicin according to a method comprising reacting diethylaminosulfur trifluoride (hereinafter abbreviated as DAST) with such a protected derivative of sisomicin whose all the amino groups and all the hydroxyl groups except the 5-hydroxyl group have been protected. Further, a literature "Journal of Carbohydrate Chemistry" Vol. 1, page 289 (1982) discloses the production of 4"-deoxy-4"-fluoro-4"-epi-kanamycin A with starting from kanamycin A, although this literature shows that the antibacterial activity of this 4"-deoxy-4"-fluoro-4"-epi-kanamycin A is lower than that of kanamycin A.
Furthermore, a literature "Tetrahedron Letters" Vol. 24, No. 17, pages 1763-1766(1983) discloses that 6"-deoxy-6"-fluorokanamycin A is produced, that 5,6"-dideoxy-5,6"-difluoro-5-epi-kanamycin A is produced and further that 5-deoxy-5-fluoro-5,4"-di-epi-kanamycin A is produced.
In this literature "Tetrahedron Letters" Vol. 24, No. 17, pages 1763-1766(1983), there is disclosed that 6"-deoxy-6"-fluorokanamycin A, 5,6"-dideoxy-5,6"-difluoro-5-epi-kanamycin A and 5-deoxy-5-fluoro-5,4"-di-epi-kanamycin A show antibacterial activities substantially as high as that of kanamycin A. Accordingly, this literature does not give any teaching that the antibacterial activity of kanamycin A can be enhanced by replacement of the 6"-hydroxyl group and/or the 5-hydroxyl group of kanamycin A by a fluorine atom. In this literature, there is not given any reference to toxicity and other biological activities of the fluorokanamycin A derivatives disclosed therein.
In another literature "Chemical Abstracts" 90, 104, 301 (1979), there is disclosed a method of producing 5-deoxy-5-fluoro-5-epi-kanamycin A, which comprises reacting DAST with a protected derivative of kanamycin A whose the amino groups and the hydroxyl groups other than the 5-hydroxyl group have been protected with conventional protective groups. But, this literature does not disclose that antibacterial activity of 5-deoxy-5-fluoro-5-epi-kanamycin A so obtained is improved over that of kanamycin A.
As will be clear from the above, hithertobefore it has not been found that the antibacterial activity of sisomicin can advantageously be improved with the cases of 5-deoxy-5-fluoro-5-epi-sisomicin and 5-deoxy-5-fluoro-sisomicin which are obtained by reacting the 5-hydroxyl group with DAST and thereby replacing the 5-hydroxyl group by a fluorine atom, with or without possible concomitant inversion of the steric arrangement of the 5-substituent. Besides, it has not yet been recognized that the antibacterial activity of kanamycin A can advantageously be enhanced with the case of the 5-deoxy-5-fluoro-5-epi-kanamycin A, as compared to the parent kanamycin A.
Thus, the present inventors have already found that 3'-deoxy-3'-fluorokanamycin A or B, 3',4'-dideoxy-3'-fluorokanamycin B and 2',3'-dideoxy-2'-fluorokanamycin A can each exhibit their improved antibacterial activities, as compared to those of their corresponding parent compounds not having the fluoro substituent. On the other hand, the present inventors have recognized that the replacemnt of the 5-hydroxyl group of sisomicin or kanamycin A by the fluoro substituent cannot bring about any advantageous improvement or enhancement in the antibacterial activity of the parent sisomicin or kanamycin A. Despiting this recognition, the present inventors have studied to synthetize 5-deoxy-5-fluorokanamycin B. In addition to our success to synthetize 5-deoxy-5-fluorokanamycin B, the present inventors have succeeded in synthetizing 5,3'-dideoxy-5-fluorokanamycin B from 3'-deoxy-kanamycin B (namely, tobramycin); 5,4'-dideoxy-5-fluorokanamycin B from 4'-deoxykanamycin B (see the "Bull. Chem. Soc. Jpn." 50, page 2362 (1977)); and 5,3',4'-trideoxy-5-fluorokanamycin B from 3',4'-dideoxykanamycin B (namely, dibekacin) (see the specification of Japanese patent application first publication "Kokai" No. 39891/88 and European patent application publication No. 0 259 014 A2).
Hithertobefore, the aminoglycosidic antibiotics have been used in clinics to exhibit such excellent curative effects in the therapeutic treatment of bacterial infections that are not obtainable with the other kinds of antibiotics, because the aminoglycosidic antibiotics are soluble in water and hence are well systemic to the tissues of human body. By virtue of this, the aminoglycosidic antibiotics are frequently utilized in the therapeutic treatment of patients sufferring from heavy bacterial infections for which the other kinds of antibiotics are not effective. In this therapeutic treatment with the aminoglycosidic antibiotics, however, intravenous injection of aqueous solutions of the aminoglycosidic antibiotics is usually and mainly made, so that the acute toxicity of the aminoglycosidic antibiotics is rapid to develop in the patients as treated, often resulting in that dosage of said antibiotics must be reduced and/or administration of said antibiotics must be interrupted. In recent years, therefore, the doctors in hospitals are likely to have an idea that the aminoglycosidic antibiotics are of high toxicity. Thus, there prevails actually such a tendency that the doctors would have a fear to the toxicity of the aminoglycosidic antibiotics and rather refrain from administering the aminoblycosidic antibiotics to such patients which should need to be therapeutically treated by administration of the aminoglycosidic antibiotics.
The present inventors have made efforts for 10 years or more in the past to solve the problem that the toxicity of the aminoglycosidic antibiotics is reduced. During recent investigations, the present inventors incidentally have discovered that the above-mentioned 5-deoxy-5-fluorokanamycin B now synthetized and its analogues show a more or less reduced toxicity (LD.sub.50 value of ca. 135 mg/kg) upon intravenous injection of them. With regard to a reason why the introduction of a fluorine atom in the 5-position of kanamycin B and its analogues can reduce the toxicity of kanamycin B etc., through any mechanism, the present inventors have studied it with groping in the dark. As an outcome, however, the present inventors have now reached in getting a presumption that the 5-fluoro substitutent can result in a reduction in the basicity of the 3-amino group of kanamycins and consequently result in a reduction in the toxicity of kanamycins.
On the basis of this discovery, the present inventors have now presumed that, in general, if there can be synthetized such 5-deoxy-5,5-difluoro derivatives of the aminoglycosidic antibiotics in which two fluoro substituents have been introduced into the 5-position of the aminoglycosidic antibiotics, new semi-synthetic aminoglycosidic antibiotics having a further reduced toxicity can be provided.